The mammalian target of rapamycin (mTOR) is a central growth controller. Recent studies have elucidated a conserved signaling pathway consisting of TSC1/TSC2-Rheb-mTOR. TSC1 and TSC2 are two tumor suppressor genes mutated in the tuberous sclerosis. The TSC1/TSC2 complex functions as a GTPase activating protein (GAP) to inhibit the Rheb small GTPase, which is a potent activator of mTOR. This signaling pathway integrates a wide range of extracellular and intracellular signals to regulate cell growth. mTOR activity is rapidly and dramatically regulated by the availability of cellular energy and amino acids. Previous studies have established that the TSC-mTOR pathway plays a critical role in the coordination between cell growth and nutrient availability at the cellular level. The major focus of this proposal is to investigate the function of TSC- Rheb-mTOR pathway in organismal energy balance and to elucidate the mechanism of this pathway in regulation of leptin signaling, appetite control, and energy expenditure. We will use mouse genetics and cell biological techniques to achieve these goals. The specific aims for this proposal are: Aim 1. To determine the function of TSC1 in POMC neurons in appetite and metabolic control and obesity Aim 2. To determine the function of TSC1 in AGRP/NPY neurons in regulation of appetite Aim 3. To elucidate the mechanism of mTOR activation in inducing leptin resistance and hyperphagia Aim 4. To determine the effect of low mTOR activity on food intake, metabolism, obesity, leptin sensitivity, and resistant to high fat diet-induced obesity. PUBLIC HEALTH RELEVANCE The TSC-mTOR pathway plays a major role in hormonal and nutritional signals to regulate cell growth. This proposal will investigate the function of TSC-mTOR in affecting leptin signaling and appetite control. The information generated from this project will provide new insights into to appetite regulation, obesity, and diabetes.